PIK3CA Mutational Analysis in Formalin-Fixed, Paraffin-Embedded Archival Tissues of Urothelial Carcinoma of Urinary Bladder
Main Article Content
Abstract
Objective: Urothelial carcinoma of the urinary bladder is the fourth most common cancer in males in
the United States. In addition to mutations in FGFR3, TP53, AKT1, TSC1, and PTEN genes, mutations
in PIK3CA have been also described in urothelial carcinomas, preferentially in low-grade tumors. Herein,
we evaluated the presence of PIK3CA mutations in exons 1, 9, and 20 in 21 urothelial carcinomas of the
urinary bladder. Methods: Patients were treated by radical cystectomy without neoadjuvant chemotherapy.
Representative tissue blocks (1 for each case) were selected. We used a pinpoint DNA extraction technique
from formalin-fixed, paraffin-embedded and mutational analysis using the polymerase chain reaction (PCR)
assay coupled with sequencing of targeted exons. Patients included 15 men and 6 women, with a median age
of 68 years (range, 42 to 76 years), with 3 noninvasive and 18 invasive urothelial carcinomas. Noninvasive
carcinomas included 1 case each of low-grade papillary urothelial carcinoma, high-grade papillary urothelial
carcinoma, and urothelial carcinoma in situ (CIS). Invasive tumors included 3 pT1, 5 pT2, 6 pT3, and 4 pT4
urothelial carcinomas. Results: We did not find mutations in the analyzed exons of the PIK3CA gene, in
any of the 21 urothelial carcinomas. The preponderance of invasive high-grade and high-stage tumors could
explain the absence of identifiable mutations in our cohort. Conclusions: PIK3CA mutations as prognosti-
cators of outcome or predictors of therapeutic response await further evaluation.
Article Details
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References
Ahmedin Jemal. Cancer statistics, 2015. CA
Cancer J. Clin., 65(1):5–29, January 2015.
[2] George J Netto. Molecular diagnostics in uro-
logic malignancies a work in progress. Arch.
Pathol. Lab. Med., 135(5):610–621, 2011.
[3] George J Netto and Jonathan I Epstein. Ther-
anostic and prognostic biomarkers: genomic ap-
plications in urological malignancies. Pathology,
42(4):384–394, 2010.
[4] Margaret A Knowles, Fiona M Platt, Rebecca L
Ross, and Carolyn D Hurst. Phosphatidylinosi-
tol 3-kinase (PI3K) pathway activation in blad-
der cancer. C
5] T L Yuan and L C Cantley. PI3K pathway alter-
ations in cancer: variations on a theme. Onco-
gene, 27(41):5497–5510, 2008.
[6] Elena Lopez-Knowles, Silvia Hernandez, Nuria
Malats, Manolis Kogevinas, Josep Lloreta, Al-
fredo Carrato, Adonina Tard ́on, Consol Serra,
and Francisco X Real. PIK3CA mutations
are an early genetic alteration associated with
FGFR3 mutations in superficial papillary blad-
der tumors. Cancer Res., 66(15):7401–7404,
2006.
[7] Fiona M Platt, Carolyn D Hurst, Claire F
Taylor, Walter M Gregory, Patricia Harnden,
and Margaret A Knowles. Spectrum of phos-
phatidylinositol 3-kinase pathway gene alter-
ations in bladder cancer. Clin. Cancer Res.,
15(19):6008–6017, 2009.
[8] Lucie C Kompier, Irene Lurkin, Madelon N M
van der Aa, Bas W G van Rhijn, Theo H van der
Kwast, and Ellen C Zwarthoff. FGFR3, HRAS,
KRAS, NRAS AND PIK3CA mutations in blad-
der cancer and their potential as biomarkers
for surveillance and therapy. PLoS One, 5(11),
2010.
[9] David Lindgren, Attila Frigyesi, Sigurdur Gud-
jonsson, Gottfrid Sj ̈odahl, Christer Hallden, Gu-
nilla Chebil, Srinivas Veerla, Tobias Ryden,
Wiking Mansson, Fredrik Liedberg, and Mat-
tias Hoglund. Combined gene expression and
genomic profiling define two intrinsic molecular
subtypes of urothelial carcinoma and gene signa-
tures for molecular grading and outcome. Can-
cer Res., 70(9):3463–3472, 2010.1
[10] Gottfrid Sj ̈odahl, Martin Lauss, Sigurdur Gud-
jonsson, Fredrik Liedberg, Christer Halld ́en,
Gunilla Chebil, Wiking Mansson, Mattias
H ̈oglund, and David Lindgren. A systematic
study of gene mutations in urothelial carcinoma;
inactivating mutations in tsc2 and pik3r1. PLoS
One, 6(4), 2011.
[11] Chao Nan Qian, Kyle A Furge, Jared Knol,
Huang Dan, Chen Jindong, Karl J Dykema,
Eric J Kort, Aaron Massie, Kean Khoo Sok,
Kristin Vanden Beldt, James H Resau, John
Anema, Richard J Kahnoski, Hans Morreau,
Philippe Camparo, Eva Comperat, Mathilde Si-
bony, Yves Denoux, Vincent Molinie, Annick
Vieillefond, Charis Eng, Bart O Williams, and
Tean Teh Bin. Activation of the PI3K/AKT
pathway induces urothelial carcinoma of the re-
nal pelvis: Identification in human tumors and
confirmation in animal models. Cancer Res.,
69(21):8256–8264, 2009.
[12] Reza R Serizawa, Ulrik Ralfkiæ r, Kenneth
Steven, Gitte W Lam, Sven Schmiedel, Joachim
Schuz, Alastair B Hansen, Thomas Horn, and
Per Guldberg. Integrated genetic and epigenetic
analysis of bladder cancer reveals an additive di-
agnostic value of FGFR3 mutations and hyper-
methylation events. Int. J. Cancer, 129(1):78–
87, 2011.
[13] Marta Duenas, Monica Martınez-Fernandez,
Ramon Garcıa-Escudero, Felipe Villacampa,
Miriam Marques,
Cristina Saiz-Ladera,
Jose Duarte, Victor Martınez, Ma Jose
Gomez, M a Luisa Martın, Manoli Fernandez,
Daniel Castellano, Francisco X. Real, Jose L.
Rodriguez-Peralto, Federico De La Rosa, and
Jesus M. Paramio. PIK3CA gene alterations
in bladder cancer are frequent and associate
with reduced recurrence in non-muscle inva-
sive tumors. Mol. Carcinog., pages n/a–n/a,
December 2013.
[14] The Cancer Genome Atlas Research Net-
work. Comprehensive molecular characteriza-
tion of urothelial bladder carcinoma. Nature,
507(7492):315–22, March 2014.
[15] Sherri Z Millis, David Bryant, Gargi Basu,
Ryan Bender, Semir Vranic, Zoran Gatalica,
and Nicholas J Vogelzang. Molecular profiling
of infiltrating urothelial carcinoma of bladder
and nonbladder origin. Clin. Genitourin. Can-
cer, 13(1):e37–49, February 2015.
[16] Philip H Kim, Eugene K Cha, John P Sfakianos,
Gopa Iyer, Emily C Zabor, Sasinya N Scott,
Irina Ostrovnaya, Ricardo Ramirez, Arony Sun,
Ronak Shah, Alyssa M Yee, Victor E Reuter,
Dean F Bajorin, Jonathan E Rosenberg, Niko-
laus Schultz, Michael F Berger, Hikmat A
Al-Ahmadie, David B Solit, and Bernard H
Bochner. Genomic Predictors of Survival in Pa-
tients with High-grade Urothelial Carcinoma of
the Bladder. Eur. Urol., August 2014.